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Human Mesenchymal Stromal Cells Engineered to Express Collagen VII Can Restore Anchoring Fibrils in Recessive Dystrophic Epidermolysis Bullosa Skin Graft Chimeras

Petrova, A; Georgiadis, C; Naso, G; Fleck, R; Allison, L; McGrath, J; Dazzi, F; ... Qasim, W; + view all (2020) Human Mesenchymal Stromal Cells Engineered to Express Collagen VII Can Restore Anchoring Fibrils in Recessive Dystrophic Epidermolysis Bullosa Skin Graft Chimeras. Journal of Investigative Dermatology , 140 (1) 121-131.e6. 10.1016/j.jid.2019.05.031. Green open access

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Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a debilitating genodermatosis caused by loss-of-functionmutations inCOL7A1encoding type VII collagen (C7), the main component of anchoring fibrils at thedermaleepidermal junction. With no curative treatments presently available, retrovirally transduced autolo-gous epidermal grafts and intradermal lentivirally engineered fibroblast injections are being investigated.Alternative approaches aim to infuse allogeneic mesenchymal stromal cells (MSCs) to provide a more gener-alized treatment for RDEB. We investigated whether healthy human MSCs could be engineered to overexpressC7 and correct RDEB in a human:murine chimeric model. Initially, engineered MSCs incorporated ex vivo intoRDEB grafts, their presence confirmed by fluorescence in situ hybridization, revealed recovery of function ofthe dermaleepidermal junction with no signs of blister formation. Importantly, the detection of anchoringfibrils by transmission electron microscopy corroborated structural recovery. Next, MSCs cotransduced toexpress C7 and luciferase were delivered intradermally into grafted RDEB skin, resulting in localized MSCpersistence with deposition of de novo C7 at the site. Notably, C7 expression was sufficient to restoreanchoring fibril density to normal levels. In contrast, intravenously injected engineered MSCs were unde-tectable within grafts and lacked anchoring fibril reconstitution. Our data suggest that although localizedcorrection may be achievable using engineered MSCs, strategies for systemic administration require furthermodeling.

Type: Article
Title: Human Mesenchymal Stromal Cells Engineered to Express Collagen VII Can Restore Anchoring Fibrils in Recessive Dystrophic Epidermolysis Bullosa Skin Graft Chimeras
Event: 22nd Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT)
Location: Washington, DC
Dates: 29 April 2019 - 02 May 2019
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jid.2019.05.031
Publisher version: https://doi.org/10.1016/j.jid.2019.05.031
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10079083
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